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Nomifensine

 

Nomifensine

Nomifensine
Systematic (IUPAC) name
(±)-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-8-amine
Clinical data
Legal status
  • (Prescription only)
Routes of
administration
Oral
Pharmacokinetic data
Biological half-life 1.5-4 hours
Excretion Kidney (88%) within 24 hours[1]
Identifiers
CAS Registry Number  N
ATC code N06
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
ChEBI  Y
ChEMBL  Y
Chemical data
Formula C16H18N2
Molecular mass 238.328 g/mol
 N   

Nomifensine (Merital, Alival) is a norepinephrine-dopamine reuptake inhibitor, i.e. a drug that increases the amount of synaptic norepinephrine and dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters.[2] This is a mechanism of action shared by some recreational drugs like cocaine and the medication Tametraline (see DRI). Research showed that the (S) isomer is responsible for activity.[3]

The drug was developed in the 1960s by Hoechst AG (now Sanofi-Aventis),[4] who then test marketed it in the United States. It was an effective antidepressant, without sedative effects. Nomifensine did not interact significantly with alcohol and lacked anticholinergic effects. No withdrawal symptoms were seen after 6 months treatment. The drug was however considered not suitable for agitated patients as it presumably made agitation worse.[5][6] In January 1986 the drug was withdrawn by its manufacturers for safety reasons.[7]

Some case reports in the 1980s suggested that there was potential for psychological dependence on nomifensine, typically in patients with a history of stimulant addiction, or when the drug was used in very high doses (400–600 mg per day).[8]

In a 1989 study it has been investigated for use in treating adult ADHD and proven successful.[9] In a 1977 study it has not proven of benefit in advanced parkinsonism, except for depression associated with the parkinsonism.[10]

Contents

  • Clinical uses 1
  • Side effects 2
  • Synthesis 3
  • See also 4
  • References 5

Clinical uses

Nomifensine was investigated for use as an antidepressant in the 1970s, and was found to be a useful antidepressant at doses of 50–225 mg per day, both motivating and anxiolytic.

Side effects

During treatment with nomifensine there were relatively few adverse effects mainly renal failure, paranoid symptoms, drowsiness or insomnia, headache, and dry mouth. Side effects affecting the cardiovascular system included tachycardia and palpitations, but nomifensine was significantly less cardiotoxic than the standard triciclyc antidepressants.[11]

Due to the risk of a risk of haemolytic anaemia, the U.S. Food and Drug Administration (FDA) withdrew approval for nomifensine on March 20, 1992. Nomifensine has subsequently been withdrawn from the Canadian and UK markets as well.[12] Some deaths were linked to immunohaemolytic anemia caused by this compound although the mechanism remained unclear.[13]

In 2012 structure–affinity relationship data (compare SAR) were published.[14]

Synthesis

Nomifensine synthesis:[15][16] GB 1164192  corresp to G. Ehrhart et al., U.S. Patent 3,577,424 (1969, 1971, both to Hoechst).

2-Nitro-N-methylbenzylamine with phenylacetyl bromide to give 3. Catalytic hydrogenation over Raney Nickel to reduce nitro group, then sodium borohydride reduces keto group to alcohol 4. H2SO4 for ring formation to 5.

See also

References

  1. ^ Heptner W, Hornke I, Uihlein M (April 1984). "Kinetics and metabolism of nomifensine". The Journal of Clinical Psychiatry 45 (4 Pt 2): 21–5.  
  2. ^ Brogden, R. N.; Heel, R. C.; Speight, T. M.; Avery, G. S. (1979). "Nomifensine: A Review of its Pharmacological Properties and Therapeutic Efficacy in Depressive Illness". Drugs 18 (1): 1–24.  
  3. ^ 'Chirality and Biological Activity of Drugs' page 138
  4. ^ US patent 3577424, "4-Phenyl-8-Amino Tetrahydroisoquinolines", issued 1971-05-04, assigned to Farbwerke Hoechst 
  5. ^ Habermann, W. (1977). "A Review of Controlled Studies with Nomifensine, Performed Outside the UK". British Journal of Clinical Pharmacology 4 (Suppl 2): 237S–241S.  
  6. ^ Yakabow, A. L.; Hardiman, S.; Nash, R. J. (1984). "An Overview of Side Effects and long-term Experience with Nomifensine from United States Clinical Trials". The Journal of Clinical Psychiatry 45 (4 Pt 2): 96–101.  
  7. ^ "CSM Update: Withdrawal of nomifensine". British Medical Journal (Clinical Research Ed.) 293 (6538): 41. July 1986.  
  8. ^ Böning, J.; Fuchs, G. (2008). "Nomifensine and Psychological Dependence - a Case Report". Pharmacopsychiatry 19 (5): 386–388.  
  9. ^ Shekim, W. O.; Masterson, A.; Cantwell, D. P.; Hanna, G. L.; McCracken, J. T. (1989). "Nomifensine Maleate in Adult Attention Deficit Disorder". The Journal of Nervous and Mental Disease 177 (5): 296–299.  
  10. ^ Bedard, P.; Parkes, J. D.; Marsden, C. D. (1977). "Nomifensine in Parkinson's Disease". British Journal of Clinical Pharmacology 4 (Suppl 2): 187S–190S.  
  11. ^ Hanks GW (1977). "A profile of nomifensine". British Journal of Clinical Pharmacology. 4Suppl 2: 243S–248S.  
  12. ^ "Nomifensine DB04821". Drugbank.ca. 
  13. ^ Galbaud du Fort, G. (1988). "Hematologic toxicity of antidepressive agents" [Hematologic Toxicity of Antidepressive Agents]. L'Encephale (in French) 14 (4): 307–318.  
  14. ^ Pechulis, AD; et al. (2012). "4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors". Bioorg. Med. Chem. Lett. 22 (23): 7219–22.  
  15. ^ PMID 5109496 (PubMed)
  16. ^ Zara-Kaczian, E.; Gyorgy, L.; Deak, G.; Seregi, A.; Doda, M. (1986). "Synthesis and pharmacological evaluation of some new tetrahydroisoquinoline derivatives inhibiting dopamine uptake and/or possessing a dopaminomimetic property". Journal of Medicinal Chemistry 29 (7): 1189.  
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